Penicillin 6-substituted

Chemical Modification. Chemical modification of most positions in the penicillin nucleus have been carried out and these are summarized in Table 4. Apart from acylation of 6-APA, few of these modifications have proven profitable in terms of improving the biological properties of the derived penicillins. However, one of the modifications that has led to beneficial properties is substitution at the 6a-position. 

Substitution of penicillins by 6a-methoxy was found to be compatible with an a-acidic side chain in terms of antibacterial activity, but less beneficial when the side chain contained an a-acyl or a-ureido substituent. However, analogues of the ureido penicillin VX-VC-43 (Table 2) containing a 6a-methoxy substituent (10) were found to combine good stabiUty to P-lactamase and relatively high antibacterial activity (37). Following an extensive program to identify other 6a-substituents that would stabilize the acyl and ureido series of penicillins, the 6a-formamido series (11) represented by formidacillin (BRL 36650) (Table 2) was developed (38). 

The early chemistry leading to these derivatives was originally carried out via the 6a-(methylthio) derivative (17) which was prepared by way of a Schiff s base (39). The 6a-thiomethyl group could then be displaced by various nucleophiles giving rise to 6a-methoxy or other 6a-substituted penicillins. A stereo-specific one-step introduction of a methoxy group at C-6 in penicillins provided a simple entry to 6a-methoxy penicillins (40) in yields ranging from 50—62%. 

A number of di- and trisubstituted hydrazides of penicillin and cephalosporin derivatives were prepared to study the effect of A-substitution on ease of oxidative cleavage. ... 

When written in this form, it should be apparent that penicillins can be diversified by substituting different groups in place of R. The penicillin class of antibiotics does, in fact, contain members that have different R groups. We will examine these later in the chapter and describe the strategies used to generate penicillins with different substitutions. 

Staphylococcus aureus cells can acquire large DNA fragments containing the mecA gene which encodes a complete new penicillin binding protein 2A (PBP 2A), as part of a transposon. PBP2A can substitute the natural set of penicillin-sensitive PBPs thereby mediating a complete cross resistance to all (3-lactam antibiotics. 

A second mechanism of resistance involves alterations in PBPs which affect binding of /3-lactams. These changes have been found to occur by multiple substitutions through recombination rather than point mutations. Acquired penicillin resistance in Strep, pneumoniae is because of such gene mosaics which code for an altered yet functional PBP with reduced affinity for penicillin. Sections of the susceptible PBP gene have been replaced by other DNA sequences, presumably via transformation. 

Sheehan, l.C. Johnson, D.A. (1954) The Synthesis of Substituted Penicillins and Simpler Structural Analogs. VIII. Phthalimidomalonaldehydic Esters Synthesis and Condensation with Penicillamine. Journal of the American Chemical Society, 76, 158-160. 

Penicillin G 24 million units/24 h IV in four to six equally divided doses may be used in place of nafcillin or oxacillin if strain is penicillin susceptible (minimum inhibitory concentration 0,1 mcg/mL) and does not produce /5-lactamase vancomycin should be used in patients with immediate-type hypersensitivity reactions to beta-lactam antibiotics (see Table 37-3 for dosing guidelines) cefazolin may be substituted for nafcillin or oxacillin in patients with non-immediate-type hypersensitivity reactions to penicillins... 

Craniotomy S. aureus, 5. epidermidis Cefazolin 1 g x 1 or cefotaxime 1 g x 1 Trimethoprim-sulfamethoxazole (160/800 mg) IV x 1 can be substituted for patients with penicillin allergy IA... 

In contrast, with penicillins, cephalosporins, and monobactams where the substituents are cis to each other across the C3 - C4 bond, clockwise rotation can occur without conflict with protein side chains, and will leave the path open for the water molecule to attack and hydrolyze the ester group in B (Scheme 10). Thus, czs-substituted monobactam, as well as penicillins and cephalosporins are rapidly hydrolyzed by class C enzymes (Scheme 10). If this rotation could be prevented by a suitable structural modification, the access of the water molecule to the ester bond will be blocked, which would result in increased stability of the acyl-enzyme complex. 

The first equation could be integrated analytically and the result substituted into the second equation which may not be integrable. Therefore, the plotted solution was obtained by numerical integration of the pair. Both the cells and the penicillin producing entity reach steady state in a few hundred hours... 

Now we turn to a discussion of the influence of a-substitution at C(6) or C(7) on the chemical reactivity of the lactam ring (Table 5.4,B). This substitution has been introduced mainly to improve lactamase stability (see Sect. 5.2.2.2). The insertion of an additional a-substituent at C(6) or C(7) of penicillins or cephalosporins, respectively, has a relatively small effect on the rate of base hydrolysis [82] [83], 6a-Methoxypenicillin is hydrolyzed at a rate that is approximately half that observed for the unsubstituted parent penicillin. This decrease is due mainly to unfavorable steric interaction between the... 

Penicillins C(6a)-substitution Cephalosporins C(7a))-substitution Inductive and steric effects Steric effect of R = MeO => approx, twofold decrease Steric effect of R = Me => ca. 10-fold decrease Decreased [73][82][83]... 

O R Substitution of lactam N-atom Basicity of leaving group amine, electron-with-drawing substituents in amino moiety Increases with basicity Monobactams are ca. 100 times less reactive than penicillins with leaving groups of similar basicity [76] [90]... 

This reaction occurs not only in bicyclic lactams, but also in monobac-tams. Indeed, intramolecular nucleophilic amino attack has also been observed in an arylglycine-substituted monobactam (Fig. 5.8,b) [84b], However, ampicillin (see below, 5.43, Fig. 5.14), which also carries an a-amino side chain in the 6/3-position, does not exhibit such an enhanced rate. This difference in reactivity has been attributed to the steric hindrance of both the geminal Me groups and H-C(3), which impedes the attack by the a-amino group at the /3-face [84a], In contrast, penicillins with an amino substituent in the 6/3-acylamido side chain show an intermolecular reaction resulting in the formation of oligomers (see Sect. 5.2.5). 

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